Reactivation of the Epstein-Barr virus (EBV) may result in systemic lupus erythematosus (SLE) in at-risk individuals, according to a study in relatives of SLE patients.
The findings also revealed that gene variants previously associated with EBV infection are implicated in the risk of developing SLE.
The research, “Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals,” was published in the journal Annals of the Rheumatic Diseases.
EBV is one of the most common viruses in humans. It remains dormant in immune B-cells upon infection, but may reactivate occasionally, triggering an antibody response to the viral capsid antigen (VCA) and the early antigen (EA). As such, blood samples may be used to identify who is experiencing, or has recently experienced, viral activation.
Prior studies have shown that SLE patients have higher levels of EBV-infected cells, indicating more frequent viral reactivation. Still, whether it may be a cause or consequence of SLE development remains unknown.
Also unknown is if EBV infection/reactivation is associated with genetic variants linked to SLE. That possibility has been suggested by studies showing single nucleotide polymorphisms (SNPs) — variations in a single nucleotide, the building blocks of DNA — in the IL10, CD40 and CR2 genes, which provide instructions for generating proteins involved in B-cell survival, differentiation, and infection by EBV.
Seeking to address these knowledge gaps, a team from of the Oklahoma Medical Research Foundation (OMRF) analyzed 436 unaffected relatives of SLE patients (nearly 75% of European American descent) to find if they ultimately would develop the disease. Clinical information and blood samples were collected at baseline and at the follow-up visit.
Over about six years, 56 participants (13%, mean age 47.4 years) developed SLE. To find why this happened, investigators measured the levels of viral-specific antibodies and assessed SNPs in IL10, CD40, CR2, and TNFAIP3, a gene associated with SLE but not with EBV infection.
Results showed that the participants who developed SLE had higher baseline levels of antibodies against VCA and EA than those who did not develop this disease or had antinuclear (ANA) antibodies (a type of autoantibody that indicates autoimmune disorders).
Such a difference was not found when comparing the participants who later had SLE with relatives who did not develop this disease, but had ANA autoantibodies at baseline. Among participants not developing SLE, those with ANA autoantibodies had higher levels of antibodies against VCA and EA than relatives without such autoantibodies.
“These data suggest that increased EBV reactivation … may contribute to generation of autoantibodies, eventually contributing to autoimmunity,” the scientists wrote.
The analysis then revealed that having increased levels of antibodies targeting VCA and EA was significantly associated with developing SLE, irrespective of having ANA autoantibodies, sex, race, or age. A similar higher risk was found when compared with a group of 122 unrelated controls.
The findings also showed a greater risk of having SLE in a subset of individuals with a specific variant of IL10 (rs3024493). Two other SNPs, in CD40 (rs4810485) and CR2 (rs17615), also affected the association between anti-VCA antibody levels and developing SLE.
“These data suggest that the genetic predisposition to SLE, as is expected in relatives of patients with SLE, influences the immune response to a latent EBV infection,” the investigators wrote.
Judith James, MD, PhD, the study’s senior author and OMRF’s vice president of clinical affairs, said in a press release “These findings will help us define those at high risk so we can monitor these people more closely to prevent damage and to identify participants for lupus prevention studies.”
“It will also allow us to follow up on what EBV is doing to the immune system and, hopefully, to understand what is causing lupus,” James said.
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